: This grant proposes to explore the hypothesis that Alzheimer's disease (AD) is a systemic disease caused by a chronic ATP deficiency resulting from diminished blood flow reactivity or defective glucose metabolism. Progressive damage to the nonregenerative central nervous system neurons is manifested early in the CNS because of the susceptibility of neurons to low blood flow and the limited ability of neurons to regenerate and to maintain mitochondrial enzymes. Specifically, we will investigate the role of systemic perfusion reactivity and systemic carbohydrate metabolism in AD. These hypotheses will be tested by experimental protocols including: (1) measurement of the deficit in acetylcholine neurons in AD by quantification of physostigmine stimulation of cerebral blood flow using high resolution PET with 122I-HIPDM; (2) measurement of endothelium-dependent vasodilatation of peripheral limb resistance vessels in AD patients in response to tourniquet-induced (blood pressure cuff) ischemia using a Doppler analysis method developed in previous; (3) evaluation of kinetics of 18F-fluorodeoxyglucose in exercising skeletal muscle of AD using positron emission tomography; (4) in vivo 4T magnetic resonance studies of oxidative phosphorylation potential in AD patients' (5) in vitro glucose metabolism studies using 14C glucose in leukocytes; and (6) mitochondrial function assays of leukocytes in AD and controls. This proposal involves 284 different patients and subjects in 405 in vivo and in vitro non-invasive studies. The procedures are currently validated technologies using unique resources at Lawrence Berkeley National Laboratory. New critical experiments in this proposal are the method of performing in vivo studies of peripheral vessel relaxivity, the in vivo skeletal muscle metabolism studies using FDG-PET, and the in vivo skeletal muscle oxidative phosphorylation potential studies utilizing 4T magnetic resonance spectroscopy.